Novel compounds
a technology of compound and compound, applied in the field of new compounds, can solve the problems of affecting the phosphorylation of p38 mapks or jnks, affecting the utility of p38 map kinase inhibitors in the treatment of human chronic inflammatory diseases, and early generations of compounds were highly toxi
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example 1
N-(4-(4-(3-(3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)-3-fluorophenoxy)pyridin-2-yl)-2-methoxyacetamide
[0587]
[0588]To a solution of CDI (424 mg, 2.62 mmol) in dry DCM (5.0 mL) under N2 and was added solid 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine (600 mg, 2.62 mmol) in four equal portions over 10 min and the resulting yellow solution maintained at RT for 16 hr. An aliquot of this solution (0.4 mL, 0.21 mmol) was added to a solution of Intermediate B1, (26 mg, 80% pure, 0.071 mmol) in dry DCM (0.5 mL) and the reaction mixture kept at RT for 16 hr and then quenched by the addition of MeOH (1.0 mL). After 5 min the mixture was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, 4 g, EtOAc in isohexane, 0-50% gradient elution) to afford impure product as a colourless oil. This material was dissolved in EtOAc (1.0 mL) and precipitated by the addition of isohexane (10 mL). The supernatant was decanted and the solid was purified by flash column chroma...
example 2
N-(4-(4-(3-(3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)-3-(methylsulfonyl)phenoxy)pyridin-2-yl)-2-methoxyacetamide
[0589]
[0590]To a solution of CDI (424 mg, 2.62 mmol) in dry DCM (5.0 mL) under N2 and was added solid Intermediate A1 (600 mg, 2.62 mmol) in four equal portions over 10 min and the resulting yellow solution kept at RT for 16 hr. An aliquot (1.4 ml, 0.65 mmol) of this solution was added to a solution of Intermediate B2 (138 mg, ˜80% purity, 0.314 mmol) in dry DCM (2.0 mL) and the reaction mixture was maintained at RT for 16 hr. A second aliquot of the CDI adduct (0.40 mL, 0.21 mmol) was added and the mixture was warmed to 35° C. for a further 24 hr. The reaction mixture was quenched by the addition of MeOH (1.0 mL) and after 10 min was evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 12 g, EtOAc in isohexane, 0-100% gradient elution) to afford impure product as a colourless oil. This material was taken up into EtOAc (2.0 mL) and then ...
example 3
N-(4-(4-(3-(3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)-3-(trifluoromethyl)phenoxy)pyridin-2-yl)-2-methoxyacetamide
[0591]
[0592]To a solution of CDI (1.06 g, 6.54 mmol) in dry DCM (10.0 mL) under N2 and was added solid Intermediate A1 (1.50 g, 6.54 mmol) in four equal portions over 10 min and the resulting yellow solution was stirred for 16 hr at RT. An aliquot of this solution (0.75 mL, 0.49 mmol) was added to a solution of Intermediate B3, (80 mg, ˜75% purity, 0.18 mmol) in dry DCM (1.0 mL) and the reaction mixture was maintained at RT for 16 hr. The reaction was quenched by the addition of MeOH (1.0 mL) and after 10 min the mixture was evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 12 g, EtOAc in isohexane, 0-100%, gradient elution). The crude product so obtained taken up into EtOAc and isohexane (10 mL) added. The precipitate was collected by filtration to afford the title compound, Example 3, as a pale orange solid (36 mg, 33%); Rt 5.25 mi...
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